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Pathophysiology > W.7: Hyperlipidemias > Flashcards

W.7: Hyperlipidemias Flashcards

1
Q

Structure of lipoproteins

A
  • Non polar core (mainly triglycerol and cholesteryl ester)

- A single surface layer of amphipathic phospholipid and cholesterol molecules

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2
Q

Polar groups of lipoproteins face towards what surface?

A

Polar group face outward to the aqueous medium

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3
Q

The protein moiety of a lipoprotein is known as an

A

Apolipoprotein/apoprotein

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4
Q

HDL is rich in..?

A

Proteins

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5
Q

LDL is rich in…

A

Cholesterol

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6
Q

Chylomicrons and VLDL have lots of..

A

Triglycerides

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7
Q

Function of apoA-I

A
  • HDL structural protein
  • LCAT activator
  • RCT (reverse cholesterol transport)
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8
Q

Function of apoA-II

A

HL (hepatic lipase) activation

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9
Q

Function of apoA-IV

A

TG metabolism, LCAT activator, diet response

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10
Q

Function of apoB-100 and apoB-48

A

Structural protein of all LP except HDL, Binding to LDL receptor

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11
Q

Function of apoC-I

A

Inhibit Lp binding to LDL R, LCAT activator

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12
Q

Function of apoC-II

A

LpL (lipoprotein lipase) activator

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13
Q

Function of apoC-III

A

LpL (lipoprotein lipase) inhibitor, antagonizes apoE

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14
Q

Function of apoE

A

B/E receptor ligand (*E2:IDL, E4: Diet responsivity)

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15
Q

Where is apolipoprotein B synthesized?

A

The rough ER

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16
Q

Where is apolipoprotein B incorporated into lipoproteins?

A

In the smooth ER

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17
Q

What happens in abetalipoproteinemia?

A

Lipoproteins containing apo B are not formed -> lipid droplets accumulate in the intestine and liver

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18
Q

Catabolism of chylomicrons

A

Fatty acids are transferred to tissues -> lipoprotein lipase (LPL) converting it to a chylomicron remnant -> goes to the liver (enters through remnant receptor (LRP)

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19
Q

Specific function of lipoprotein lipase

A

It’s function results in the loss of ~90% of the triacylycerol of chylomicrons and in the loss of apo C (returns to HDL)

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20
Q

How are chylomicrons taken up to the liver?

A
  • By receptor mediated endocytosis (mediated by apoE)
  • (cholesterol esters and triacylglycerols are hydrolyzed and metabolized)
  • Hepatic lipase: ligand to facilitate remnant uptake, hydrolyzes remnant triacylglycerol and phospholipid
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21
Q

Where are chylomicrons produced?

A

Intestinal cells

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22
Q

Where is VLDL produced?

A

In the liver by hepatic parenchymal cells

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23
Q

Which apolipoprotein is essential for VLDL formation?

A

Apo B-100

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24
Q

Lipoprotein lipase in reaction with VLDL

A

Results in the loss of ~90% of the triacylglycerol of VLDL and in the loss of apoC

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25
Q

What are the remnants of VLDL called?

A

IDL

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26
Q

How is IDL taken up by the liver?

A
  • Liver takes it up directly via the LDL receptor (apoB-100, E)
  • May also be converted to LDL
27
Q

What is defective in familial hypercholesterolemia?

A

The LDL receptor

28
Q

Where is HDL synthesized?

A

Both synthesized and secreted from both liver and intestine

29
Q

Apo C and apo E are synthesized in the …. for use by HDL

A

In the liver, transferred from liver HDL to intestinal HDL

30
Q

Function of LCAT (lecithin cholesterol acyl transferase)

A

Lecithin + cholesterol -> cholesteryl esters + lysolecithin

31
Q

Function of the class B scavenger receptor B1 (SR-B1)

A
  • In the liver and steroidogenic tissues: binds HDL via apoA-I -> cholesterol esters selectively delivered to cells
  • In the tissues: mediates the acceptance of cholesterol form the cells by HDL -> HDL takes it to the liver for excretion via bile
32
Q

Describe the HDL cycle

A
  1. HDL3 is generated from discoidal HDL by LCAT
  2. HDL3 accepts cholesterol from the tissues via SRB1
  3. Cholesterol is esterified by LCAT -> increasing the size of the particles and forming the less dense HDL2
  4. HDL3 reformed either after selective delivery of cholesteryl ester to the liver via SRB1 OR by hydrolysis of HDL2 phospholipid and triacylglycerol by hepatic lipase
33
Q

Function of ABCA1/ABCG1 in general

A

Couple the hydrolysis of ATP to the binding of a substrate, enabling it to be transported across the membrane

34
Q

Specific function of ABCA1

A

Transfer cholesterol from cells to poorly lipidated particles such as pre-HDL or apoA-I (which are then converted to HDL3 via discoidal HDL)

35
Q

Role of CETP (cholesteryl ester transfer protein)

A

-Transfers cholesteryl esters to LDL
-Transfer triglycerides to HDL3
(?)

36
Q

5 functions of HDL

A
  1. scavenging action: HDL scavenges extra cholesterol from peripheral tissues by reverse cholesterol transport
  2. Competes with LDL for membrane binding (preventing internalization of LDL cholesterol in smooth m. of arterial walls) -> with help of apoE
  3. Contributes its apoC and E to nascent VLDL and chylomicrons
  4. Stimulates prostacyclin synthesis by endothelial cells (prevents thrombus formation)
  5. Helps in removal of macrophages from the arterial wall
37
Q

Mutant gene in familial hupercholesterolemia

A

LDL receptor

38
Q

Mutant gene in Familial defective ApoB

A

ApoB

39
Q

Mutant gene in familial combined hyperlipidemia

A

Not known

40
Q

Mutant gene in familial type III

A

ApoE

41
Q

Management of very high triglycerides (>500mg/dl)

A
  • Goal of therapy: prevent acute pancreatitis
  • Very low fat diets
  • TG lowering drug: fibrate or nicotinic acid
  • Reducing TG before LDL lowering
42
Q

Role of PCSK9 in the development of hypercholesterolemia

A

It’s secreted by the liver and it is thought to promote degradation of LDL receptor

43
Q

Definition of secondary hyperlipidemias

A

Hyperlipidemias that develop in notmolipidemic patients due to other diseases (60-90% incidence)

44
Q

Dysfunctional HDL is possibly caused by?

A

Myeloperoxidase (product of an inflammatory enzyme) target mainly ApoA1 and converts HDL into a pro-inflammatory non-functional HDL

45
Q

Primary hyperlipoproteinemias (5)

A
  • Type I (familial hyperCHYLOMICRONemia)
  • Type II (familial hyperCHOLESTEROLemia)
  • Type III (dysbetalipoproteinemia)
  • Familial combined hyperlipidemia
  • Familial hypertriglycerdemia
46
Q

What is deficient in Type I (familial hyperchylomicronemia), what is characteristic for it and what are the symptoms?

A
  • Deficient: LPL or ApoC2
  • Can find severe hypertriglyceridemias (Plasma TG >1000mg/dL)
  • Symptoms: Lipidemia retinalis (eyes), eruptive xanthomata (skin), hepatosplenomegaly and increased risk for pancreatitis
47
Q

Causes of Type II (familial hypercholesterolemia)

A
  • LDL receptor mutation (67%)
  • Unknown (16,7%)
  • Defect in ApoB (14%)
  • PCSK9 gain of function (2,3%)
48
Q

Heterozygous familial hypercholesterolemia

A
  • One LDL-receptor gene is affected
  • Affects about 1 in 500 people
  • TC 9-14 mmol/L
49
Q

Homozygous familial hypercholesterolemia

A
  • Both LDL-receptor genes affected
  • Affects about 1 in 1 million people
  • TC 15-30 mmol/L
50
Q

Defect, abnormal concentrations and signs of Type III (dysbetalipoproteinemia)

A
  • ApoE2 homozygosity
  • Cholesterol increased (>300mg/dL - >7.5mmol/L)
  • TG increased (>443mg/dL - >5mmol/L)
  • Signs: palmar cresae xanthomas, tuberous and tuberoruptive xanthomas (skin), premature atherosclerosis
51
Q

Common secondary hyperlipidemias: Obesity - why?

A

Inc. adipose tissue -> more FFA -> liver TG synthesis -> VLDL inc. -> LDL cholesterol inc. -> HDL dec.

52
Q

Common secondary hyperlipidemias: DM type I - why?

A
  • Inc. efflux of ketone bodies + FFA from adipose tissue due to inc. lipolysis -> liver -> inc. synthesis of TG and VLDL -> inc. LDL -> dec. HDL
    (Only inappropriately treated patients develop hyperlipidemia)
53
Q

Common secondary hyperlipidemias: DM type II - why?

A
  • Patients usually have dyslipidemia
  • Insulin resistance ->
    1. LPL activity dec., CHY inc., VLDL inc.
    2. Efflux of inc. FFA from adipose tissue -> liver -> inc. synthesis of TG and VLDL -> inc. LDL -> dec. HDL
    2. Se.LDL normal or inc., but small-LDL inc. (Metabolic-X syndrome)
54
Q

Common secondary hyperlipidemias: Hypothyroidism - why?

A
  • Usually phenotype II/a.

- Synthesis of LDL receptor dec. -> Inc. Se.Ch/Se.LDL and IDL

55
Q

Common secondary hyperlipidemias: Alcohol - why?

A
  • Se.TG inc., Se.HDL inc., gammaGT inc. (metabolism of ethanol) -> inc. beta-ox. -> synthesis of inc. TG
  • Activity of LPL inc. -> Se.HDL inc.
56
Q

Common secondary hyperlipidemias: Nephrotic syndrome - why?

A

Proteinuria -> hypoalbuminemia -> synthesis of inc. proteins/apo-lipoproteins (apoB) -> hyperlipidemia

57
Q

Common secondary hyperlipidemias: Chronic renal failure - why?

A
  • Usually phenotype IV
  • Hyperlipidemia
  • Se. LPL activity dec.
58
Q

Common secondary hyperlipidemias: Kidney transplanted patients - why?

A

Immunosuppression -> hypertriglyceridemias

59
Q

Common secondary hyperlipidemias: Hemodialysis

A

Increased Se.Lp(a)

60
Q

Common secondary hyperlipidemias: Hepatic diseases

A

Primary biliary cirrhosis and other obstructive liver diseases -> Inc. Se.cholesterol (LP-X)

61
Q

Common secondary hyperlipidemias: Pregnancy

A
  • Estrogen -> synthesis of VLDL inc. -> Se.TG inc., Se.Ch inc. -> hepatic lipase activity dec.
  • Patient should be treated if other primary hyperlipidemia is present but only with diet!
62
Q

Common secondary hyperlipidemias: Cushing syndrome

A

Glucocorticoids -> synthesis of VLDL inc. -> Se.LDL inc. mildly

63
Q

Common secondary hyperlipidemias: Glycogen storage diseases

A

-Von Gierke disease: Mutation of g-6-P -> inappropriate glucose mobilisation -> efflux of inc. FFA from adipose tissue -> liver synthesis of TG inc.

Pathophysiology (14 decks)

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